SiRNA in MSC-derived exosomes silences CTGF gene for locomotor recovery in spinal cord injury rats

Abstract

Background How to obtain a small interfering RNA (siRNA) vector has become a moot point in recent years. Exosomes (Exo) show advantages of long survival time in vivo, high transmission efficiency, and easy penetration across the blood-spinal cord barrier, renowned as excellent carriers of bioactive substances. Methods We applied mesenchymal stem cell (MSC)-derived exosomes as the delivery of synthesized siRNA, which were extracted from rat bone marrow. We constructed exosomes-siRNA (Exo-siRNA) that could specifically silence CTGF gene in the injury sites by electroporation. During the administration, we injected Exo-siRNA into the tail vein of SCI rats, Results In vivo and in vitro experiments showed that Exo-siRNA not only effectively inhibited the expressions of CTGF gene, but quenched inflammation, and thwarted neuronal apoptosis and reactive astrocytes and glial scar formation. Besides, it significantly upregulated several neurotrophic factors and anti-inflammatory factors, acting as a facilitator of locomotor recovery of rats with spinal cord injury (SCI). Conclusions In conclusion, this study has combined the thoroughness of gene therapy and the excellent drug-loading characteristics of Exo for the precise treatment of SCI, which will shed new light on the drug-loading field of Exo.

Therapeutic Effect of Exosomes Derived From Stem Cells in Spinal Cord Injury: A Systematic Review Based on Animal Studies

“…A total of 701 related articles were obtained. After excluding the literature based on the exclusion criteria, eventually 32 studies were included (19)(20)(21). The entire screening process is summarized in Figure 1.…”

“…Among the included 32 studies, only two studies were controlled studies ( 29 , 33 ), and the remaining 30 studies were randomized controlled studies. The species of animals included SD rats ( 19 – 21 , 28 – 37 , 39 , 40 , 42 – 44 , 46 , 47 , 49 – 53 , 55 , 56 ), Wistar rats ( 41 , 54 ), and C57BL/6 mice ( 38 , 45 , 48 ); gender included male ( 28 , 30 – 32 , 38 – 45 , 49 , 53 , 54 ) and female ( 19 , 20 , 29 , 33 , 34 , 36 , 37 , 46 – 48 , 50 – 52 , 55 , 56 ), two studies did not report the sex of the animals ( 21 , 35 ); the weights of animals were between 150 ( 41 ) and 300 g ( 20 , 44 ), the weight of the mouse was between 17 and 22 g ( 48 ), and seven of the studies did not report the weight of the animals ( 21 , 29 , 30 , 38 , 42 , 45 , 50 ); age was between 6 ( 38 , 44 , 45 , 50 , 51 ) and 12 weeks ( 47 , 56 ), and nine of the studies did not report the age of the animals ( …”

“…Among the included 32 studies, only two studies were controlled studies (29,33), and the remaining 30 studies were randomized controlled studies. The species of animals included SD rats (19-21, 28-37, 39, 40, 42-44, 46, 47, 49-53, 55, 56), Wistar rats (41,54), and C57BL/6 mice (38,45,48); gender included male (28, 30-32, 38-45, 49, 53, 54) and female (19, 20, 29, 33, 34, 36, 37, 46-48, 50-52, 55, 56), two studies did not report the sex of the animals (21,35); the weights of animals were between 150 (41) and 300 g (20,44), the weight of the mouse was between 17 and 22 g ( 48), and seven of the studies did not report the weight of the animals (21,29,30,38,42,45,50); age was between 6 (38,44,45,50,51) and 12 weeks (47, 56), and nine of the studies did not report the age of the animals (19, 21, 35-37, 42, 46, 51, 52); samples size were between 10 (51) and 100 (41); models of SCI included contusion (20, 21, 28-32, 34-53, 56), hemisection (54), and transection (19,33,55); the types of exosomes included the exosomes of bone marrow mesenchymal stem cells of SD rats (BMSCs-Exo) (20, 21, 28, 30, 34-37, 39, 42-44, 47, 49, 52, 53, 56), BMSCs-Exo of Wistar rats (41,54), BMSCs-Exo of human (19,33,…”

“…For example, Huang et al tracked exosomes through an animal imaging system and found that most of the exosomes still gather in the liver and lungs, and are finally swallowed by monocytes. In fact, only a limited number of exosomes reach the spinal cord ( 20 , 21 ). However, Chen et al reported that exosomes are much smaller than stem cells and are easily accessible through the blood-brain barrier without being captured by liver or lung tissue ( 22 ).…”

Exosomes as bio-inspired nanocarriers for RNA delivery: preparation and applications

“…Recently researchers illustrated that silencing the CTGF gene via siRNA-loaded MSCs-derived exosomes effectively reduced the inflammation and neuronal apoptosis at the injured area of the spinal cord. Besides, it has been shown that loading miRNA into the exosome structure can easily induce some processes such as promoting cancer cell apoptosis, regulating lipid metabolism, and promoting angiogenesis [ 114 ].…”